The goal of the proposed studies is to elucidate the relationship between the enterohepatic circulation of bile acids, intestinal lipid absorption, and hepatic VLDL production. In order to accomplish that goal, the following aims will be addressed in this project. 1: To test the hypothesis that the ileal apical sodium bile acid transporter (Asbt) is the major mechanism for intestinal bile acid absorption. For these studies, an ileal apical bile acid transporter null mouse model has been generated. This unique animal model of Primary Bile Acid Malabsorption will be used to quantify the Asbt's role in the enterohepatic circulation of bile acids. 2: To test the hypothesis that the Asbt and an intact enterohepatic circulation of bile acids are essential for efficient intestinal cholesterol and fat absorption. For these studies, the Asbt null mouse will be used to determine quantitative relationships between bile acids and intestinal lipid absorption. 3: To test the hypothesis that increased bile acid malabsorption through decreased Asbt function will protect mice from atherosclerosis. In these studies, the Asbt null allele will be introduced into two commonly used atherosclerosis susceptible backgrounds of mice, C57BL/6 Apoe -/- and C57BL/6 Ldlr-/- to directly test the hypothesis that the predicted lipid-lowering effects of decreased Asbt activity will be protective against diet-induced atherosclerosis. 4: To test the hypothesis that disruption of the enterohepatic circulation of bile acids will directly increase hepatic VLDL triglyceride production. The isolated mouse liver perfusion system will be used to directly test the hypothesis that a decreased bile acid return to the liver directly stimulates VLDL triglyceride production.